Prostate cancer is the most commonly diagnosed cancer in U.S. men and the second leading cause of death in this population. We have recently discovered that a discrete sweet gum extract (LIS-100), prepared from Liquidambar styraciflua L. fruits may provide a novel effective treatment for this disease. Our preliminary data has shown that this product produces simultaneous inhibition of mTOR and PI3K/Akt pathways in hormonally refractive disease. mTOR inhibitors are showing promise as useful targeted chemotherapeutic agents in many malignancies, including late stage prostate cancer. However, unexpected feedback activation of Akt by mTOR inhibitors has become a barrier for the effective use of this class of drugs. Our preliminary data indicates that LIS- 100 was found to effectively inhibit proliferation of prostate cancer (IC50 -1.85 ug/ml), especially androgen independent PC3 cells. At concentrations as low as 2.5 ug/ml, LIS- 100 almost totally shut down the expression of effectors of the mTOR pathways, yet did not cause activation of Akt. In fact, it simultaneously inhibited phosphorylation of Akt in PC3 cells, suggesting that LIS-100 is dual inhibitor of PI3K/Akt and mTOR pathways. This exciting discovery prompted this proposal to evaluate the efficacy, mechanisms and safety of LIS-100 in androgen-dependent more metastatic prostate cancer (LNCaP-LN4) and androgen independent PC3 cells as well as antitumor activity in associated orthotopic xenograft models. LNCaP-LN4 cells express a functional AR, which is similar to majority of human AIPC, and hence will serve a better model representing the aggressive late stage of prostate cancer. It is our hypothesis that effective use of mTOR inhibitors must include a means of inhibiting activation of Akt. We believe that LIS-100 may represent one of the most effective dual inhibitors of mTOR and PI3K/Akt pathways yet described and, as such, may be very effective in treatment of late stage prostate cancer. This grant is designed to thoroughly explore the mechanisms of action of LIS100 in inhibition of proliferation of hormone sensitive as well as hormone refractory prostate cancer. Furthermore, studies aimed at determining it's efficacy in vivo against xenograft tumors will be used to assess its potential as a future clinical candidate. PUBLIC HEALTH RELEVANCE: The proposed research involves studies of an extract of fruit of a "sweet gum" tree that we have found to be very effective for treatment of hormone refractory prostate cancer. Initial promising work in human cell cultures will be expanded to look at specific mechanisms of action of the extract as well as to test the product against human prostate tumors in immunocompromised mice. This will determine if sufficient promising data can be obtained to warrant clinical evaluation of the extract in men with advanced hormone refractory prostate cancer.